The goal of this proposal is to gain insight in the basis for the biological effects of antitumor drugs, including the basis for acute cytoxic effects, chronic toxic effects, mutagenesis and carcinogensis. The approach is to investigate mechanisms for DNA damage and repair in human cells related to antitumor drugs. Specific aims include development of methods for such studies, including: 1. Use of the alpha sequence of human DNA as an indicator of DNA damage and repair. 2. Development of new methods for detection of stable DNA adducts. 3. Development of methods for analysis of the enzymology of repair of lesions induced by antitumor drugs. Specific questions addressed are: 1. What is the sequence dependence of damage by these agents to naked alpha DNA? 2. What is the nature of the damage to the alpha DNA of intact cells? Do the agents cause strand breaks, alkali-labile lesions, base modifications, crosslinks or stable adducts in DNA of intact cells? What is the stability of the lesions? Are there specific repair pathways for these lesions? Do defects in DNA repair, such as those characteristic of cells derived from patients with inherited syndromes such as Xeroderma Pigmentosum (XP) or Ataxia Telangectasia (AT) affect the rate of repair of a damage?